Altered Myocardial Fatty Acid Metabolism in Obesity

描述（由申请人提供）： 肥胖（体重指数> 30 kg/m2）影响超过4300万美国人，并且特别是当涉及腹部或内脏（AO）时，与增加的心脏病发病率和死亡率相关。基于肥胖实验模型的研究结果和我们对AO患者的初步研究，我们假设在AO患者中，脂肪分解增加导致脂肪酸释放到血浆中增加，导致脂肪酸递送到心脏增加。特别是当与胰岛素抵抗结合时，这导致心肌脂肪酸代谢增加。我们进一步假设心肌基质代谢的这种变化与心室收缩和舒张功能的异常有关。此外，我们认为，在进一步增加脂肪酸输送的条件下，中性脂质的心肌蓄积增加，这反过来又可能被心室收缩和舒张功能的进一步下降所阻碍。我们将通过一系列高度复杂的实验来证明或反驳这一假设，这些实验利用PET定量心肌底物代谢、超声心动图测量左心室收缩和舒张功能以及稳定同位素测量全身脂肪酸和葡萄糖动力学，这些实验在一组经过良好筛选的瘦型和II类AO受试者中进行。将在各种条件下获得测量值，旨在评估中度体重减轻、胰岛素利用率和血浆脂肪酸水平对AO中心肌底物代谢、机械功能和全身底物代谢之间关系的影响。如果成功的话，资助申请中描述的研究结果将证实，在肥胖实验模型中观察到的心肌脂肪酸代谢异常也见于AO患者。这些信息将为更有针对性的研究奠定基础，这些研究旨在阐明导致这些异常的机制，并可能为AO患者带来显着的临床益处。

DESCRIPTION (provided by applicant): Obesity (body mass index > 30 kg/m 2) affects more than 43 million Americans, and particularly when involving the abdomen or viscera (AO), is associated with increased cardiac morbidity and mortality. Based on the results of studies in experimental models of obesity and our preliminary studies in humans with AO, we hypothesize that in humans with AO, increased lipolysis leading to increased release of fatty acids into the plasma results in increased fatty acid delivery to the heart. Particularly when combined with insulin resistance this results in an increase in myocardial fatty acid metabolism. We further hypothesize that this shift in myocardial substrate metabolism is associated with abnormalities in ventricular systolic and diastolic function. Moreover, we believe that under conditions that further increase fatty acid delivery, myocardial accumulation of neutral lipids is increased, which in turn may be paralleled by a further decline in ventricular systolic and diastolic function. We will prove or disprove this hypothesis by performing a series of highly-complex experiments that utilize PET quantification of myocardial substrate metabolism, echocardiographic measurements of left ventricular systolic and diastolic function and stable isotopic measurements of whole-body fatty acid and glucose kinetics in a well-screened group of lean and Class-lI AO subjects. The measurements will be obtained under a variety of conditions designed to assess the influence of moderate weight loss, insulin availability, and plasma fatty acid levels on the relationship between myocardial substrate metabolism, mechanical function and whole-body substrate metabolism in AO. If successful, the results of the studies described in the grant application will provide confirmation that the abnormalities in myocardial fatty acid metabolism observed in experimental models of obesity are seen in humans with AO. Such information will form the basis for more targeted studies designed to elucidate the mechanisms responsible for these abnormalities and potentially result in significant clinical benefit for humans with AO.